ABSTRACT Currently there are more than 37 million people living with HIV worldwide, and with the advent of antiviral therapy (ART) infected peoples are living much longer. According to the 2013 CDC HIV Surveillance Report, 53,000 people 65 and older are living with HIV in the U.S., and life expectancies of the HIV-infected are likewise increasing in developing countries. As HIV infected individual ages, their probability of developing HIV associated neurological disease (HAND) and/or Alzheimer's disease (AD) increases. Over 50% of ART-treated HIV infected individuals eventually develop HAND; however, the prevalence of AD and the impact of HIV on AD in an aging population is unknown. In fact, HIV infection may be a risk factor for AD because their shared pathways of neuro-inflammation, accelerated CNS aging, and neurocognitive decline. These relationships will be investigated in the proposed study. Our parent grant entitled ?The impact of Cannabis on inflammation and HIV-1 reservoirs in Zambia? (R01 DA044920-01) is collecting and analyzing postmortem samples from HIV-1 positive Cannabis users, for an investigation of the impact of cannabinoid exposure on inflammation in HIV-1 patients and the resulting impact on HIV-1 reservoirs in both treated aviremic and untreated viremic cases. We will utilize this supplement to develop a new research direction on HIV, cannabis use and AD. This is a logical extension of our unique current study on cannabis that has already collected over 120 postmortem sample sets from individuals infected with HIV, those using cannabis, as well as controls. The overall objective of our supplement study is to analyze the current collection and prospective cases from the next 12 months to investigate relationships between HIV, inflammation, cannabis use and AD in human tissues. We hypothesize that HIV infection will enhance AD development due to chronic inflammation, and cannabis usage will reduce inflammation and severity of AD-associated neuropathologies. We will test the hypothesis through the following two aims: 1) To analyze the archived brain tissues from our parent study and those collected prospectively for AD-associated neuropathogy; 2) To correlate cannabis usage with the severity of AD-associated neuropathologies, HIV infection, and levels of inflammation. Our study will lead to a better understanding of the impact of the long-term infection by HIV on AD, and will stimulate additional research, including any potential therapeutic use of cannabis for these diseases.